scholarly journals Rap1GAP Mediates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Inhibiting Autophagy and Increasing Oxidative Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Yan Gao ◽  
Di Zhao ◽  
Wen-zhi Xie ◽  
Tingting Meng ◽  
Chunxiao Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Generation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Neonatal Cardiomyocytes ◽  
And Oxidative Stress

Abnormal autophagy and oxidative stress contribute to angiotensin II- (Ang II-) induced cardiac hypertrophy and heart failure. We previously showed that Ang II increased Rap1GAP gene expression in cardiomyocytes associated with hypertrophy and autophagy disorders. Using real-time PCR and Western blot, we found that Rap1GAP expression was increased in the heart of Sprague Dawley (SD) rats infused by Ang II compared with saline infusion and in Ang II vs. vehicle-treated rat neonatal cardiomyocytes. Overexpression of Rap1GAP in cultured cardiomyocytes exacerbated Ang II-induced cardiomyocyte hypertrophy, reactive oxygen species (ROS) generation, and cell apoptosis and inhibited autophagy. The increased oxidative stress caused by Rap1GAP overexpression was inhibited by the treatment of autophagy agonists. Knockdown of Rap1GAP by siRNA markedly attenuated Ang II-induced cardiomyocyte hypertrophy and oxidative stress and enhanced autophagy. The AMPK/AKT/mTOR signaling pathway was inhibited by overexpression of Rap1GAP and activated by the knockdown of Rap1GAP. These results show that Rap1GAP-mediated pathway might be a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which could be a potential target for the future treatment of cardiac hypertrophy and heart failure.

Abstract 1476: Angiotensin II Induced Hypertrophic Response And Oxidative Stress Is Attenuated In Mice Lacking The Gene For Tnf-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Srinivas Sriramula ◽  
Nithya Mariappan ◽  
Elizabeth McILwain ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Collagen Type ◽  
Resonance Spectroscopy ◽  
Type I ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Tnf Α ◽  
And Oxidative Stress

Tumor necrosis factor-alpha (TNF-α) and angiotensin II (Ang II) play an important role in the pathophysiology of cardiovascular disease in part by inducing the cardiac hypertrophic response and oxidative stress. Recently we demonstrated that angiotensin induced hypertensive response is attenuated in mice lacking the gene for TNF-α. In this study, we examined whether Ang II induced cardiac hypertrophy and increased oxidative stress is mediated through TNF-α. Methods and results: Male TNF-α (−/−) and age matched control (WT) mice were subcutaneously implanted with osmotic minipumps containing Ang II (1 μg/kg/min) or saline for 14 days. Human recombinant TNF-α was injected in one group of TNF-α (−/−) mice (10 μg/kg/day) for 14 days. In WT+Ang mice, a temporal increase in blood pressure was observed during the study as measured by radio telemetry transmitters. At the end of the study, echocardiography revealed an increase in thickness and dimensions of left ventricle (LV) and decreased fractional shortening (%FS) in WT+Ang mice. Real time RT-PCR showed that Ang II- infusion resulted in an increase in heart/bodyweight ratio and of cardiac hypertrophy markers ANP and BNP, and profibrotic genes Collagen Type I, Collagen Type II, and TGF-β in WT mice. Electron Spin resonance spectroscopy revealed an increase in total ROS, superoxide and peroxynitrite in the WT+ANG mice when compared to control WT mice. However, these changes were all attenuated in TNF-α (−/−)+Ang mice. Ang II infusion also increased significantly the mRNA expression of gp91Phox, NOX-1, NOX-4 and AT1R in the LV of WT mice, but not in TNF-α (−/−) mice. Interestingly, injection of TNF-α in the TNF-α (−/−) mice, treated with Ang II resulted in increased cardiac hypertrophy and oxidative stress. Conclusions: Findings from the present study suggest that TNF-α plays an important role in the development of cardiac hypertrophy and oxidative stress in Ang II-induced hypertension.

scholarly journals The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure

2019 ◽  
Vol 316 (1) ◽  
pp. H186-H200 ◽  
Author(s):  
Ju Youn Beak ◽  
Hong Soon Kang ◽  
Wei Huang ◽  
Page H. Myers ◽  
Dawn E. Bowles ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Orphan Receptor ◽  
Ang Ii ◽  
Pathological Hypertrophy

The nuclear receptor retinoic acid-related orphan receptor-α (RORα) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORα has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORα regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORα in the context of pathological cardiac hypertrophy and heart failure, we used the “staggerer” (RORαsg/sg) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORα. RORαsg/sg and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced RORα in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORαsg/sg mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain- and loss-of-function experiments were consistent with the discovery that RORα inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORα directly repressed IL-6 transcription. Loss of RORα function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr705), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. RORα was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORα protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-α (RORα) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORα leads to enhanced IL-6 expression and NF-κB nuclear translocation. RORα maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORα is reduced in failing mouse and human hearts.

Abstract 097: EGF Receptor And ER Stress Mediate End-organ Damage But Not Hypertension Induced By Angiotensin II In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Katherine J Elliott ◽  
Toshiyuki Tsuji ◽  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Steven Forrester ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Egf Receptor ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Egfr Activation ◽  
And Oxidative Stress

In cultured vascular smooth muscle cells (VSMC), a metalloprotease ADAM17-dependent EGF receptor (EGFR) activation mediates ERK1/2 activation and subsequent hypertrophy induced by angiotensin II (Ang II). Both ER and oxidative stress are implicated in hypertensive end-organ damage. We hypothesized that pharmacological inhibition of EGFR may prevent end-organ damage but not hypertension in mice infused with Ang II via suppression of ER/oxidative stress. To test this hypothesis, we have evaluated Ang II-induced end-organ damage as well as hypertension in C57Bl/6 mice with or without an EGFR inhibitor erlotinib (20mg/kg/day ip) or ER stress inhibitor 4-phenyl butyric acid (PBA: 1g/kg/day in drinking water). Upon Ang II infusion (1000 ng/kg/min) for 2 weeks, control mice showed phenotypes of cardiac hypertrophy including increased HW/BW ratio (mg/g: 7.9±0.7 vs 5.7±0.6 p<0.01 n=8) and increased LVPWd assessed by cardiac echo (mm: 0.98±0.14 vs 0.69±0.05, p<0.05 n=8) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, cardiac hypertrophy and vascular remodeling were attenuated in mice with Ang II plus erlotinib or PBA; HW/BW ratio (6.8±0.6 or 6.2±0.6 n=8), and cardiac echo (LVPWd: 0.65±0.07 or 0.80±0.07 n=8) compared with saline infusion. Renal fibrosis observed with Ang II infusion was also attenuated in mice with Ang II plus erotinib or PBA. However, Ang II induced similar levels of hypertension in non-treated, erlotinib-treated or PBA-treated mice assessed by telemetry (MAP mmHg: 144±9 vs 149±20 or 139±4). Ang II infusion in mice enhanced ADAM17 and phospho-Tyr EGFR staining in vasculatures of heart and kidney, whereas mice with Ang II plus erlotinib or PBA had diminished phospho-Tyr EGFR staining and no ADAM17 staining in the vasculatures. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused mice with erlotinib or PBA. These data suggest that EGFR activation and subsequent ER stress enhancement are critical for end organ damage via induction of ADAM17 and oxidative stress and is independent from blood pressure regulation.

scholarly journals MicroRNA-129-5p targets keap-1 to protect against cardiomyocyte hypertrophy via Nrf2 pathway

2020 ◽  
Author(s):  
Huiming Ye ◽  
Guiyu Xu ◽  
Dexian Zhang ◽  
Rupeng Wang
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Luciferase Reporter ◽  
Cardiomyocyte Hypertrophy ◽  
Leucine Incorporation ◽  
Ang Ii ◽  
Luciferase Reporter Gene ◽  
Nrf2 Pathway ◽  
Gene Assay ◽  
And Oxidative Stress

Abstract Background: Cardiac hypertrophy is a common pathological process of many cardiac diseases and persistent cardiac hypertrophy is the main cause of heart failure and sudden cardiogenic death. It is of great value to elucidate the mechanism of cardiac hypertrophy for better prevention and treatment. Methods: The protein levels were measured by western blotting or RT-qPCR. cardiomyocytes hypertrophy was evaluated by [3H]-leucine incorporation assay. oxidative stress was measured by corresponding detection kits. The target relationship was measured by Luciferase reporter gene assay. Morphological change of cardiomyocyte was measured by immunofluorescence staining. Results: In our study, we for the first time revealed the effects and regulatory mechanism of miR-296-5p in cardiac hypertrophy in vitro . We found suppressed expression of miR-129-5p and elevated expression of keap-1 in Ang II-induced cardiomyocyte hypertrophy model. MiR-129-5p mimic effectively suppressed Ang II-induced hypertrophic responses and oxidative stress. Further experiments showed that keap-1 is a target of miR-129-5p, and miR-129-5p inhibitor promoted cardiomyocyte hypertrophy and oxidative stress by elevating keap-1. Besides, si-keap-1 mediated the activation of Nrf2 pathway, while miR-129-5p inhibitor inactivated the Nrf2 pathway by further elevating keap-1. Conclusions: MiR-129-5p mimic protects against Ang II induced cardiomyocyte hypertrophy via activating Nrf2 pathway by targeting keap-1.

scholarly journals Betulinic Acid Protects DOX-Triggered Cardiomyocyte Hypertrophy Response through the GATA-4/Calcineurin/NFAT Pathway

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 53
Author(s):  
Jung Joo Yoon ◽  
Chan Ok Son ◽  
Hye Yoom Kim ◽  
Byung Hyuk Han ◽  
Yun Jung Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Betulinic Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Generation ◽  
H9c2 Cells ◽  
Myosin Light Chain 2 ◽  
Cardiovascular Morbidity And Mortality

Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 µM) in the presence or absence of BA (0.1–1 μM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (β-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 µM. DOX-induced activation of GATA-4 and calcineurin/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

Abstract 1374: A Novel eNOS-Independent Protective Action of Statin against Angiotensin II-Induced Atrial Remodeling Via Attenuating Rac-1-Mediated Oxidative Stress

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shusuke Yagi ◽  
Masashi Akaike ◽  
Ken-ichi Aihara ◽  
Kazue Ishikawa ◽  
Takayuki Ise ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Left Atrial ◽  
Protective Action ◽  
Left Atrial Volume ◽  
Cardiomyocyte Hypertrophy ◽  
Radical Scavenger ◽  
Atrial Remodeling ◽  
Ang Ii ◽  
Anticoagulation Agents

Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation (AF) and thrombosis, especially in a condition with decreased nitric oxide bioavailability. Although antiarrhythmic and anticoagulation agents are used under these pathological conditions, these drugs are not able to ameliorate atrial remodeling. Recently, it has been reported that statins reduce the incidence of AF through attenuating atrial remodeling; however, the mechanisms have not been completely elucidated. This study was designed to determine the beneficial effect of pitavastatin (Pit) against angiotensin II (Ang II)-induced atrial remodeling and to elucidate its mechanism. eNOS knockout mice were sham-operated or infused with Ang II by an osmotic mini-pump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: Pit, tempol, a free radical scavenger, or a vehicle. Echocardiography and electrocardiography showed that Ang II infusion increased left atrial volume and caused a high incidence of AF, whereas Pit and tempol treatment prevented Ang II-induced left atrial enlargement and AF. Histological analysis showed that acceleration of Ang II-induced interstitial fibrosis, perivascular fibrosis and cardiomyocyte hypertrophy in the atrium were all attenuated by Pit and tempol treatment. Immunohistochemistry showed that Ang II down-regulated thrombomodulin and up-regulated tissue factor and plasminogen activator inhibitor-1 in the left atrium and that Pit and tempol treatment corrected the Ang II-induced thrombogenic condition. Moreover, Pit and tempol reduced Ang II-induced atrial superoxide production, detected by dihydroethidium staining, and atrial TGF- β 1 expression and Smad 2/3 phosphorylation. Activity of Rac-1-GTPase involved in the activation of NADPH oxidase in the atrium was attenuated by Pit but not by tempol. Pit exerts eNOS-independent protective actions against Ang II-induced atrial structural and electrical remodeling with enhanced thrombogenicity through suppressing Rac-1-mediated oxidative stress, leading to suppression of the TGF- β 1/Smad pathway.

Abstract 1380: Antioxidants Decrease Neuronal Angiotensin II Type 1 Receptor in Heart Failure: Inhibition of Activator Protein 1 and Jun N-Terminal Kinase

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dongmei Liu ◽  
Lie Gao ◽  
Kurtis G Cornish ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Neuronal Cell ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Nadph Oxidase Activity ◽  
Activator Protein

In a previous study, we showed that Ang II type I receptor (AT1R) expression increased in the rostral ventrolateral medulla (RVLM) of chronic heart failure (CHF) rabbits and in normal rabbits infused with intracerebroventricular (ICV) Angiotensin II (AngII). The present study investigated if oxidative stress plays a role in Ang II induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. In neuronal cell cultures, Ang II significantly increased AT1R mRNA by 153 ± 22%, P <0.01; c-Jun mRNA by 90 ± 10%, P < 0.01; NADPH oxidase activity by 126 ± 43%, P < 0.01 versus untreated cells; Tempol, Apocynin and the AP 1 inhibitor Tanshinone II reversed the increased AT1R, c-Jun expression and NADPH oxidase activity induced by AngII. We examined the effect of ICV Tempol on expression of these proteins in the RVLM of CHF rabbits. Compared to untreated CHF rabbits Tempol significantly decreased AT1R protein expression (0.88±0.16 vs. 1.6±0.29, P <0.05), phosphorylated Jnk protein (0.10±0.02 vs. 0.31±0.10, P <0.05), and phosphorylated c-Jun (0.02±0.001 vs. 0.14±0.05, P <0.05). These data suggest that Ang II induces AT1R upregulation at the transcriptional level by activation of oxidative stress and AP1 in both cultured cells and in intact brain. Antioxidant agents may be beneficial in CHF by decreasing AT1R expression through the Jnk and AP1 pathway.

Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

2006 ◽  
Vol 26 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Xin Tian ◽  
Jusan Yang ◽  
Shannon M. Dunlay ◽  
Andrew S. Peek ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Dominant Negative ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Signaling Cascade ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression

2005 ◽  
Vol 288 (2) ◽  
pp. E353-E359 ◽  
Author(s):  
Mihaela C. Blendea ◽  
David Jacobs ◽  
Craig S. Stump ◽  
Samy I. McFarlane ◽  
Cristina Ogrin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Angiotensin Ii ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Soleus Muscle ◽  
Whole Body ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Superoxide Anion Production

To evaluate the role of renin-angiotensin system (RAS)-mediated oxidative stress in insulin resistance (IR), we compared the effects of the angiotensin II (ANG II) receptor blocker (ARB) valsartan and a superoxide dismutase (SOD) mimetic, tempol, on whole body glucose tolerance and soleus muscle insulin-stimulated glucose uptake in transgenic hypertensive TG(mREN-2)27 (Ren-2) rats. Ren-2 rats and Sprague-Dawley (SD) controls were given valsartan (30 mg/kg) or tempol (1 mmol/l) in their drinking water for 21 days. IR was measured by glucose tolerance testing (1 g/kg glucose ip). IR index (AUCglucose × AUCinsulin) was significantly higher in the Ren-2 animals compared with SD controls (30.5 ± 7.0 × 106 arbitrary units in Ren-2 vs. 10.2 ± 2.4 × 106 in SD, P < 0.01). Both valsartan and tempol treatment normalized Ren-2 IR index. Compared with SD controls (100%), there was a significant increase in superoxide anion production (measured by lucigenin-enhanced chemiluminescence) in soleus muscles of Ren-2 rats (133 ± 15%). However, superoxide production was reduced in both valsartan- and tempol-treated (85 ± 22% and 59 ± 12%, respectively) Ren-2 rats. Insulin (INS)-mediated 2-deoxyglucose (2-DG) uptake (%SD basal levels) was substantially lower in Ren-2 rat soleus muscle compared with SD (Ren-2 + INS = 110 ± 3% vs. SD + INS = 206 ± 12%, P < 0.05). However, Ren-2 rats treated with valsartan or tempol exhibited a significant increase in insulin-mediated 2-DG uptake compared with untreated transgenic animals. Improvements in skeletal muscle insulin-dependent glucose uptake and whole body IR in rats overexpressing ANG II by ARB or SOD mimetic indicate that oxidative stress plays an important role in ANG II-mediated insulin resistance.

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